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Infect Immun, August 1998, p. 3832-3840, Vol. 66, No. 8
School of Biological Sciences, University of
Manchester, Manchester M13 9PT, United
Kingdom,1 and
Brussels Branch,
Ludwig Institute for Cancer Research, and Experimental Medicine
Unit, Catholic University of Louvain, Brussels,
Belgium2
Received 20 January 1998/Returned for modification 19 February
1998/Accepted 6 May 1998
Upon infection with the cecum-dwelling nematode Trichuris
muris, the majority of inbred strains of mice launch a Th2-type immune response and in doing so expel the parasite before patency. In
contrast, there are a few mouse strains which develop a nonprotective Th1-type response resulting in a chronic infection and the presence of
adult worms. Of the Th2 cytokines known to be associated with the
resistant phenotype (interleukin-4 [IL-4], IL-5, IL-9, and IL-13),
comparatively little is known about the contribution that IL-9 makes
towards the protective immune response. In this study we demonstrate
that IL-9 is expressed early during the Th2-type response and that its
elevation in vivo results in the enhancement of intestinal mastocytosis
and the production of both the immunoglobulin E (IgE) and IgG1
isotypes. In addition, elevated IL-9 levels in vivo facilitated the
loss of T. muris from the intestine. That IL-9 is
important in promoting worm expulsion was also seen following infection
of IL-9-transgenic mice, which constitutively overexpress the cytokine.
These animals displayed an extremely rapid, but immune mediated,
expulsion of the parasite. Also evident in these animals was a
pronounced intestinal mastocytosis, which was previously shown by us to
be responsible for the expulsion of the related nematode
Trichinella spiralis from these animals. Taken together with observations of IL-9 production following infection with other
helminths, the results imply that IL-9 contributes to the general mast
cell and IgE response characteristic of these infections and, more
specifically, enhances resistance to T. muris.
A clear dichotomy in immune
responsiveness to the intestinal nematode Trichuris muris is
seen upon infection of different inbred strains of mice. Those that are
susceptible (e.g., AKR mice) mount a nonprotective Th1-type response.
This results in a chronic infection in which adult worms develop,
persist, and are unable to be expelled by their host. In contrast,
resistant strains (e.g., BALB/K or C57BL/6 mice) mount a Th2-type
response which leads to a short-lived infection in which worm expulsion is initiated and completed before the adult worms develop (7, 11).
This association between Th2-type cytokines and host protection extends
to other intestinal nematode infections. Such nematodes include
Nippostrongylus brasiliensis,
Heligmosomoides polygyrus, Trichinella
spiralis, and Strongyloides venezuelensis (reviewed in reference 15). A number of investigators have
examined the contribution that an individual Th2 cytokine makes during
the protective immune response to these infections. In the main, these studies have focused on interleukin-4 (IL-4), and certainly evidence of
a strong role for this cytokine has emerged over recent years. However,
in some situations its importance is likely to stem from its role
in mediating Th2-cell development and ultimately the production of
other, perhaps important, Th2 cytokines (reviewed in reference
1). In addition, there are circumstances in which the presence of IL-4 is not critical for a resistant phenotype (2,
22). It is therefore important to evaluate the contributions of
other cytokines during the worm expulsion process.
IL-9 is one such cytokine that is produced by CD4+ T cells
during Th2-type responses in vivo, including during infections with intestinal helminths (17, 19, 37). Indeed, mice that are resistant to T. muris produce high levels of IL-9 which
negatively correlate with the Trichuris worm burden
(10, 11). However, the functional role of this cytokine
during helminth infection is not well characterized, even though
several biological targets in vitro have been elucidated. These targets
include CD4+ T cells (33, 41), bone
marrow-derived mast cells (20), B cells (5, 29),
and certain erythroid progenitors (4).
Through a variety of approaches, we have assessed the contribution that
IL-9 makes during the immune response to T. muris. We
demonstrate that IL-9 gene expression correlates with the
resistant phenotype and is expressed early following
infection. Elevating its levels in vivo results in the enhancement of
several Th2-mediated changes that are often considered
hallmarks of helminth infection. These include mucosal
mastocytosis, moderate levels of mouse mast cell protease-1
(MMCP-1) in serum, and immunoglobulin E (IgE) and IgG1 antibody
production. Moreover, elevating IL-9 levels in vivo facilitates worm
expulsion, and IL-9-transgenic mice, which constitutively overexpress
the cytokine, display extremely rapid expulsion kinetics. As IL-9 has
previously been shown to influence expulsion of the related nematode
T. spiralis (13), this study extends
knowledge of the cytokine's protective role to T. muris and suggests its importance in other intestinal nematode infections.
Animals.
AKR (H-2k), BALB/K
(H-2k), and C57BL/6
(H-2b) mice were purchased from Harlan Olac Ltd.
(Bicester, United Kingdom). IL-9-transgenic mice
(H-2q) were generated by microinjecting a
transgene construct into the pronuclei of fertilized eggs of FVB mice
as previously described (31). These FVB mice were used as
wild-type controls. The transgenic mice were generated at the Ludwig
Institute for Cancer Research, Brussels, Belgium, and then bred in the
facility at the University of Manchester, Manchester, United Kingdom.
All experimental groups consisted of four to six male animals which
were infected when they were 6 to 8 weeks old.
Parasite.
The techniques used for the maintenance,
infection, and recovery of T. muris have previously
been described (42). The E/N isolate used was originally
obtained from the Wellcome Research Laboratories, London, United
Kingdom. Mice were infected with approximately 300 T. muris eggs on day 0 and killed at various time points
postinfection (p.i.).
IL-9 complex methodology.
IL-9 was delivered in vivo to AKR
mice by intravenous injection of 10 µg of recombinant IL-9 complexed
with 50 µg of a neutralizing anti-IL-9 monoclonal antibody (2C12) on
days 7, 11, 15, and 18 p.i., using a protocol previously described
(14). Animals were killed on day 35 p.i.
IL-9-secreting T-cell line.
IL-9 levels were raised in vivo
by intraperitoneal injection of 107 TS1.G6 cells into
C57BL/6 mice 7 days prior to infection with T. muris.
These cells represent an IL-9 factor-dependent T-cell line transfected
with the IL-9 gene and constitutively secrete IL-9 in vitro. Their
administration to C57BL/6 mice in vivo has previously been described
(40). Animals were killed on day 17 p.i.
Cortisone treatment.
IL-9-transgenic mice and their
wild-type controls were given 1.25 mg of hydrocortisone-21-acetate
(Sigma Chemical Co., Poole, United Kingdom) subcutaneously on days Histology.
The cecum tip was removed at autopsy and fixed in
Carnoy's fluid for 6 h prior to processing by standard
histological techniques. Sections were stained in 0.5% toluidine blue
(pH 0.3), and the number of mast cells in 20 cecal crypt units (CCU)
was determined for each animal.
Enzyme-linked immunosorbent assay.
Levels of MMCP-1 in serum
were measured with an MMCP-1 enzyme-linked immunosorbent assay kit
purchased from Moredun Animal Health Ltd., Penicuik, United Kingdom, by
using a technique described previously (21). Briefly, rabbit
anti-MMCP was used as the capture antibody. Tenfold serial dilutions of
serum were made from 1/100 to 1/100,000 for IL-9-transgenic mice and
from 1/10 to 1/10,000 for all other strains. Horseradish
peroxidase-conjugated rabbit anti-mouse MMCP-1 was then added, and
quantification was made by reference to purified MMCP-1.
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Interleukin-9 Enhances Resistance to the Intestinal
Nematode Trichuris muris
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
3,
1, 1, and 4 p.i. Animals were killed on days 12 and 34 p.i.
RT-PCR.
BALB/K and AKR mice were infected on day 0. On days
1, 4, 11, 21, and 35 p.i., mesenteric lymph nodes (MLN) were
collected from five animals from each group and pooled, and single-cell suspensions were made as previously described (7). Cells
(5 × 106) were centrifuged at 2,000 × g for 10 min, resuspended in RNAzol B (Biogenesis,
Bournemouth, United Kingdom), snap frozen, and stored at 80°C until
use. MLN cells from an uninfected group were also taken. Total RNA was
later extracted from all samples according to the manufacturer's
instructions (Biogenesis), and reverse transcription-PCR (RT-PCR) was
performed as previously described (36). The IL-4 and
hypoxanthine-guanine phosphoribosyltransferase (HPRT) primers were
based on previously published sequences (25, 27). The IL-9
primers were designed from the genomic DNA sequence (30) and were as follows: sense, CATCCTTGCCTCTGTTTTGCT;
antisense, CGGAGAGACACAAGCAGCTGG. The amplification
program consisted of 1 min at 94°C, 1 min at the annealing
temperature, and 2 min at 72°C, for 30 cycles. The annealing
temperature for HPRT and IL-4 was 60°C, whereas that for IL-9 was
55°C. Both the cycle number and annealing temperature were previously
determined to be optimal for the primer pairs used. The number of
cycles performed was determined to be below the reaction saturation
point, enabling analysis during the linear relationship between input
RNA and PCR product. Both positive and negative controls, including
reverse transcriptase and PCR reagent blanks, were run with each
amplification. The amplified product was detected by Southern blot
analysis with specific internal probe sequences end labelled with
[
-32P]ATP. The sequences for IL-4 and HPRT have
previously been described (36). The IL-9 probe,
TCCACCGTCAAAATGCAG, was designed from its
genomic DNA sequence (30). Blots were exposed to a
storage phosphor screen and scanned on a phosphorimager (BAS 2000 TR; Fujix, Fuji, Japan). Values were individually normalized to those for
HPRT and expressed relative to those for uninfected controls, which
were arbitrarily given a value of 1.
Statistical analysis. Significant differences between experimental groups were calculated by using the Mann-Whitney U test, with P < 0.05 considered significant. All data are expressed as mean values ± standard errors (SE).
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Early IL-9 gene expression following infection of resistant mice. IL-9 is known to be produced in large quantities by in vitro-stimulated MLN cells from resistant, but not susceptible, mice following T. muris infection (11). In these earlier studies IL-9 production, in conjunction with IL-4, was evident by day 21 p.i. We wanted to look earlier than this time point and to determine the kinetics of IL-9 gene expression in comparison with those of IL-4 gene expression. We therefore infected resistant BALB/K and susceptible AKR mice with the parasite. Following establishment (day 11 infectivity: BALB/K, 95.6 worms ± 9.6; AKR, 87.0 ± 13.3), BALB/K mice commenced expulsion, which was complete by day 21 p.i. (BALB/K, 0.4 ± 0.2; AKR, 115.0 ± 13.9). In contrast, AKR mice failed to expel the parasite, harboring adult worms on day 35 p.i. (AKR, 81.6 ± 19.1).
Figure 1 shows the levels of IL-4 and IL-9 gene expression in the MLN in both strains of mice throughout infection. Clearly apparent was the ability of BALB/K mice to express both of these Th2 cytokines in response to infection. In contrast, AKR mice expressed low levels, barely above those for the uninfected controls, throughout the time period. Interestingly, in the BALB/K mice an increase in IL-9 gene expression was observed by day 4 p.i., whereas a rise in IL-4 was not observed until day 21 p.i. Therefore, elevated IL-9 gene expression correlates with the resistant phenotype and is apparent before an observed increase in IL-4 gene expression.
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Elevated IL-9 levels in vivo enhance several Th2-mediated characteristics of infection. Considering the lack of IL-9 gene expression in the susceptible AKR mice, we wanted to determine the effects of raising its levels in vivo in these animals. AKR mice were infected on day 0 and given recombinant IL-9 in the form of a complex on the days indicated. Figure 2a shows the numbers of intestinal mast cells on day 35 p.i. Clearly apparent were significantly greater numbers of intestinal mast cells in the IL-9-treated group following infection (P < 0.05). It is important to note that there was no increase in the number of mucosal mast cells in the uninfected animals following the administration of IL-9. This suggests that the cytokine may be acting in synergy with other mast cell growth factors, such as IL-3 and stem cell factor (SCF), as has been shown in vitro (18, 20).
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IL-9-transgenic mice rapidly expel T. muris. We wanted to determine the effects of IL-9 overproduction on infection with T. muris. IL-9-transgenic mice and their wild-type FVB littermates were therefore infected on day 0 and analyzed on days 13, 21, and 34 p.i. Worm burden analysis revealed that both of these strains had virtually completed expulsion by day 13 p.i. (wild type, 11.5 ± 6.0; transgenic mice, 3.8 ± 4.1), and no worms were found at the later time points (data not shown). This was surprising, because previously examined resistant mouse strains typically commence expulsion during the third week of infection (9). The expulsion kinetics are therefore very fast, for both strains, and suggest that the specific arm of the immune response may not have been involved.
We therefore measured the levels of parasite-specific IgG in serum on day 34 p.i. (Fig. 4a and b). High serum IgG1 levels in the virtual absence of IgG2a were found in the wild-type mice, indicative of a Th2-type response (10). In contrast, both parasite-specific IgG1 and IgG2a were absent in the sera of the IL-9-transgenic mice. Due to the rapid loss of the parasite, this day 34 time point may have been too late for detection. However, we failed to find any parasite-specific IgG antibody, of any isotype, at the earlier time points (data not shown). The two mouse strains therefore appear to respond differently. One possible explanation for this might be that the majority of larvae transverse through the IL-9-transgenic gut so rapidly that insufficient antigen is available for B-cell activation.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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IL-9 production is seen during Th2-type responses in vivo, including during intestinal nematode infections (15, 19, 38). One key finding from these studies is the upregulation of IL-9 gene expression early following infection. For example, a rise in the local levels of IL-9 is seen as early as 6 h following a primary infection by H. polygyrus (38), and in the case of N. brasiliensis, IL-9 gene expression is coincident with the arrival of the worms in the gut (15). Here, we analyzed for the first time the expression of this cytokine following infection with T. muris. We found a significant increase in neither the IL-9 nor the IL-4 message following infection of the susceptible AKR (Th1-type) mouse strain. However, in the resistant BALB/K strain, IL-9 gene expression was upregulated early during the Th2-type response, in accordance with the above- described model systems. We also measured the cytokines secreted by their restimulated MLN cells and found these levels to correlate with the level of message obtained (data not shown).
In the BALB/K mice the expression of IL-9 preceded that of IL-4, although further studies are needed to confirm this observation and to examine expression prior to 24 h p.i. This is an interesting observation, because CD4+ T cells are a known cellular source of IL-9, and IL-4 is known to promote IL-9 gene expression in T cells (33, 34). However, a recent study has also shown the induction of IL-9 mRNA before IL-4 message as well as the ability of IL-4 knockout mice to express the IL-9 gene (24). As their early IL-9 peak disappeared following anti-CD4 treatment, it appears that IL-4-independent regulation of IL-9 gene expression in vivo can occur. Furthermore, a non-T-cell source of early IL-9 has been described, which may help to explain its rapid production in our system (38). Investigations are needed to address this issue and to determine the role of IL-9 in subsequent Th2 cell development.
The elevation of host IL-9 levels had a significant effect on intestinal mastocytosis. It is well known that IL-9 can influence the growth of bone marrow-derived mast cells and their functional activity in vitro (6, 20). However, evidence of its role as a mast cell growth factor in vivo is only now beginning to emerge. The control of mast cell proliferation and function is complex but is believed to be under the influence of a number of cytokines, including IL-3, IL-4, and IL-10 (32, 35, 39). Whether IL-9 acts independently of these cytokines in vivo is not yet clear. In the studies detailed here, the administration of IL-9 in the absence of antigen was not sufficient to promote mastocytosis, suggesting the involvement of other factors. However, the presence of very high levels of IL-9 did appear to circumvent the need for additional cytokines: naive IL-9 transgenic mice had greatly elevated numbers of intestinal mast cells, yet no other systemic or local cytokine production was found (unpublished observations). SCF is a stromal-cell-derived factor involved in the development of mast cells in the bone marrow and their subsequent migration into the periphery (16). Interestingly, when SCF function is blocked in the transgenic animals, their intestinal mast cell numbers profoundly decrease (13). As both transgenic and wild-type mice constitutively express SCF, these findings together suggest that both IL-9 and SCF are required for the high-level mastocytosis observed (18).
The elevation of serum MMCP-1 levels following the administration of IL-9 and the high circulating levels in the IL-9-transgenic mice suggest the functional activity of the intestinal mast cells. It is known that mucosal- but not connective-tissue-type mast cells produce this protease following their activation (23). Indeed, IL-9-transgenic mice have numbers of connective-tissue-type mast cells comparable to those in their wild-type counterparts (18). Taken together, the results suggest the specific involvement of IL-9 in the development of the mucosal mast cell lineage.
The production of both IgE and IgG1 was enhanced following elevation of host IL-9 levels. IL-4 is thought to be the principal cytokine involved in their production, both in vitro and in vivo (37), although recent reports have suggested an IL-4-independent regulation of IgE production under certain circumstances (26). It is known that IL-9 can act in synergy with IL-4 to increase the secretion of both of these antibody isotypes in vitro (29). Whether IL-9 acts independently of IL-4 to promote their production in our system is unclear. The absence of a parasite-specific IgG1 response in the transgenic animals was surprising and might appear to contradict a role for IL-9 in promoting its production. Indeed, we have previously observed very high levels of this antibody following infection of IL-9-transgenic mice with T. spiralis (13). However, cortisone treatment, which allowed parasite survival, did result in the production of parasite-specific IgG1. Therefore, it appears that during a normal infection of IL-9-transgenic mice, there is insufficient antigenic stimulation for measurable antibody production, owing to the rapid worm expulsion.
An important finding from this study was the ability of IL-9 to promote the loss of T. muris from its intestinal niche. In essence, we raised IL-9 levels by three methods, with the IL-9 complex method and the transgenic system being the least and most effective systems, respectively. However, it must be stressed that the results of the latter experiment need to be treated with some caution, as the levels of IL-9 present are extraordinarily high. Therefore, the results may not reflect the role of IL-9 under physiological conditions. However, it is quite clear from the studies using IL-9 complexes and IL-9-producing T cells in vivo that raising IL-9 levels more moderately also results in changes similar to those seen in IL-9-transgenic mice. Taken together, the results of the present study present compelling evidence for an important role for IL-9 in protective immunity to helminths. The mechanisms by which IL-9 promotes resistance remain to be determined. Other studies have convincingly shown that mast cells, eosinophils, and antibody-dependent mechanisms are not essential for worm expulsion (3, 8). Certainly, in the transgenic animals the worms were expelled quickly and effectively in the absence of any detectable serum antibody response. Experiments to establish the physiology of the IL-9-transgenic gut, in terms of gut motility and fluid absorption, are under way, as this may exert an influence. As IL-9 is expressed early during the specific Th2-type response, our working hypothesis is that IL-9 helps mediate resistance through its ability to promote T-cell growth and hence potentiate Th2-cell development. Future experiments will address this issue.
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ACKNOWLEDGMENTS |
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We thank Neil Humphreys for his excellent technical support and Catherine Betts for her help and advice with the RT-PCR analysis.
The financial support of the BBSRC is gratefully acknowledged.
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FOOTNOTES |
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* Corresponding author. Present address: Department of Biological Sciences, University of Salford, Peel Building, The Crescent, Salford M5 4WT, United Kingdom. Phone: 44 161 295 4069. Fax: 44 161 295 5210. E-mail: H.Faulkner{at}biosci.salfcrd.ac.uk.
Editor: S. H. E. Kaufmann
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Abstract
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Materials & Methods
Results
Discussion
References
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